9-chloro-17 alpha-hydroxy corticosterone and process for its preparation



wterone (compound 3.).

United States Pat A 2,942,010 I Y QCHLORO-I'la -HYDROXY'h CORTIGOSTERONE AND PROCESS FOR ITS PREPARATION 1 a David Taub, Metuchem Norman I Wendler,"'Suinn1it, and C2 Stewart SnoddwJrLrPlainfieId, N.J., assignors I to Merck & Cog. Inc'., RahwayyN'J acorporation of NewLlersey V t :Nom'awing: Eiled.0ct.,31,lI9,55,. S1-.No, 52:11pm

' 6'Claims'. iterate-1:397:45

a This invention. is;v concerned generally with novel steroid compounds and with novel processes of! preparingthem. Moreparticularly, it relates to: the novel compound, 9=chloro-17a-hydroxycorticosterone an'd with-novel processesforpreparing this compoundzstarting with A anhydro-hydrocortisone acetate; The 9-chloro-17a-hy droxycorticosterone and its acetate have been found to possess a high level of cortisone-like activity. 7

The 9 chloro 17a hydroxycorticosterone, commonly called 9-chloro-hydrocortisone, can be chemically'representedyas follows: I i

CHzOH In accordancerwith the presently invented process, this compound is prepared by reacting -'A .?-anhydrohydrocortisone acetate (compound 1 hereinbelow) with. an N-chloroamide in the presence of aniner-t solvent medium thereby forming directly 9-chloro-l7a-hydroxycorticosteronelacetate (compound 2) which, upon reactionwith a hydrolyzing agent, forms 9-chloro-17a-hydroxycorticos- The reactions nidicated above may betchemically represented as .follows:

CHzOAc .Compound2 Compoundii In carrying out the presently invented process, the A -anhydro-hydrocortisone acetate (A -pregnadiene-l7a,21-diol-3,20-di0ne 21-acetate) is brought into inbe used if desired.

The large excess of N-chloroamide, and the specified reaction "conditions'are critical to this reaction; Whereas the 9-bromo analog can be prepared by reacting A anhydro-hydrocortisoneacetate with approximately an'equimolecular quantity of N-bromacetamide, attempts to prepare 9-chloro-l7ot-hydroxycorticosterone acetate by reacting 1.0 mole ofA anhydro hydrocortisone acetatewith 1.5 moles each of'N chlorsuccinimide and per chloric acid atthe optimum reaction temperature fail to give an appreciable amount of 9'-chloro-17m-hydroxycorti- A 4 -anhydro-hydrocortisone acetate) has 'failed to give a significant yield of desired product when thereaction temperature isbelow this preferred range (e.g'. 151 0.), and has resulted in extensive decomposition and tar formation when the reaction temperature is slightly more elevated than that range ,(e.g. 55 C.).

. The N-chloroamide and pferchloricacid are-ordinarily used on an equimolar basis, that is, the same molar excess of'each is employed. If desired, however, the, relative proportions of these two reactants can be varied independently within the preferred rangeprovidingthat the excess .ofeach of these reactants is sufiicient to provide between about- 5 and 15 moles of each reactantpermole of A -anhydro-hydrocortisone acetate.

The reaction is conveniently conducted by. adding the N-chloroamide and perchloric acid (in the form ofian aqueous solution) to. a suspension of the A -anhydrohydrocortisone acetate in theinert solvent medium. As the solvent medium, it is preferred to employ acyclic ether solvent such as .dioxane, a dialkyl-alkanoylamide such as dimethylformamide, dimethylacetamide, and the like. The resulting-suspension is maintained at a reaction temperature within the specified orange, preferably with moderate stirring, until an essentially homogenous solution is obtained, at which time the reaction is sub stantially complete.

,..After the completion -of.the reaction, excess reagents areconveniently decomposed. by the additionof reducing I agents such as sodium. sulfite,- sodium bisulfite, andathe like. 'lhe 9chloro- 17a-hydroxycorticosterone acetate is conveniently recovered-from therresulting mixture; by

' partially-evaporating the solvents, whereupon the; product obtained asa crystalline ma'ss; .Altematirvely,1,follovsi ing decomposition of the excess N-chloroamide and perchloric acid, the reaction mixture is diluted with a saturated salt solution, whereupon the 9-chloro-l7a-hydroxycorticosterone acetate crystallizes and may be recovered these examples are given for purposes of illustration 7 not of limitation.

, Example 1 A mixture of 386 mg. of M -pregnadiene-17,21- diol-3 20-dione 2l-acetate (1 millimol), 20 ml. of dioxane, and 1.35 g. of N-chlorsuccinimide (8.9 millimol, 88% pure) is cooled to a temperature of about 15 to 20 C. To the cooled mixture is added 10 ml. of 1.04 N aqueous perchloric acid (10.4 millimol), and the resulting white suspension is stirred at a .temperature of about 30 C. for a period of approximately three hours, at the end of which time most of the material dissolves to give alight yellow solution. The reaction solution is cooled to a temperature of about10 C., a sufiicient amount of aqueous sodium sulfite solution is added to discharge the excess N chlorsuccinimide, and the resulting mixture is adjusted to neutrality by the addition. of aqueous sodium bicarbonate solution. Most of the solvent is evaporated from the resulting mixture under reduced pressure while maintaining the temperature of the mixture within a range of aboutv 25 to 30 C. The residual materlal 1s triturated T': acetate and reacting the Ian-er compound with a with 150 ml. of water, and the partly non-crystalline mass completely solidifies on scratching. The light-yellow granular. solid is recovered by filtration, Washed with water, and air dried to give 395 mg. of crude material.

s material is trlturated with ether, and the crystalllne mately five to fifteen moles each of an N chloroamlde material is recovered by filtration and dried to give 267 mg. of substantially pure 9-chloro-A -pregnene-11fl,17a, 2l-triol-3,20-dione 21-acetate; M.P. '196201 C. decl; yield approximately 60% of theory.

Example 2 7 v A mixture of 386 mg; of A -pregnadiene-170:,21 diol-3,20-dione' 2 1-acetate (1 millimol), 20 ml. of dioxane, and 1.35 g. of N-chlorsuccinimide (8.9 millimol',

887 ure is cool dt t t f b tlS a P e a empera ure 0 a on to moles each of.N-chloroam1de and'perchloric acid per 20" C. To. the cooled mixture is added 10 ml. of 1.04 N aqueous perchlorieacid (10.4 millimol), and the resulting white suspension is stirred at atemperature of about 30 C. for a period of approximately three hours,

atth endof h'ht' I e W m lme most of the material dlssolves nadiene-l7a,2l-diol-3,20-dione 21-acetate with N-chlorotogive a light yellow solution. The re'actionsolution is cooled to a temperature of about 10 C., and sufiicient amount of aqueous sodium sulfite solution is added todis charge the excess N-chlorsuccinimide. To the resulting mixture is added a'saturated aqueous solution of sodium r chloride, and the crystalline material which precipitates is recovered by filtration, dried and recrystallized from a mixture of acetone and ether to give substantially pure 9 chloro A -pregnene-11;3,17a,21-triol-3,20-dione 21- acetate.

Example 3 I 100 mg. 9-chloro-A -pregnene-11B,17a,21-triol-3,2O-dione 21-acetate is dissolved in methanol containing one molecular equivalent of sodium methoxide, and the resulting solution is allowed to stand at room temperature for about 10 minutes. The hydrolysis reaction solution is diluted with water, and the precipitated material is recovered by filtration, dried, and purified by recrystallization from a mixture of ethyl acetate and ether to give substantially pure 9 chloro 17a-hydroxycorticos'terone (9-chloro-N- pregnene-l 1B,17a,21-triol-3,20-dione) Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are tobe considered as part of this invention.

We claim:

1. The process which comprises reacting A -preg"- nadiene-17a,21-diol-3,29-dione 2l-acy1ate with approxi-- mately five to fifteen moles each of an N-chloroamide and perchloric acid per mole of A -pregnadiene compound at a temperature within the range of 25-'45 C- thereby forming 9-chloro-.l7a-hydroxycorticosterone 2iacylate, and reacting the latter compound with a hydrolyzing agent to produce 9-chloro-17a-hydroxycorticosterone.

2. The process which comprises reacting A' -pr'egnadiene-l7u,21-diol-3,20-dione 2'1-alkanoate with approximately five to fifteen moles each of an N-chloroamide and perchloric acid per mole of A -pregnadiene compound at a temperature within the range of 25-45 C. thereby forming 9-chloro-17a-hydroxycortiscosterone 21- alkanoate, and reacting the latter compound with a hydrolyzing agent to produce 9-chloro-17e-hydroxycorticdse terone. t

3. The process which comprises reacting A -preg 7 nadiene-17a,2l-diol-3,20-dione 21-acetate with approximately five to fifteen moles each of an N-chloroamide and perchlo'ric acid per mole of A -pregnadiene compound at a temperature within the range' of 25-45 C. thereby forming -9-'chloro-17a-hydroxycorticosterone 21- drolyzing agent to produce 9-chloro-17a-hydroxycorticosterone.

4. The process which comprises reacting A -pregnadiene-17a,21-diol-3,20-dione 21-acylate with approxiand perchloric acid per mole of A -pregnadiene com: pound at a temperature within the range of 25'45 C. thereby forming 9-chloro-17ot-hydroxycorticosterone 21 acylate. 'j

S. The process which comprises reacting A -pregnadiene-l7a,21-diol-3,20-dione 21-alkanoate' with an 'N- chloro'amide and perchloric acid, said reaction being conducted by bringing together at a temperature within the range of about 25-45 C. approximately -5 to15 mole of A -pregnadiene-17a,21-diol-3,20-dione 21- alkanoate, thereby forming 9-chloro-17a-hydroxycorticosterone alkanoate.

6. The process which comprises reacting-A -pregsuccinimide and perchloric acid, said reaction being conducted by bringing together approximately 5 to 15 moles each of N-chlorsuccinimide and perchloric acid per mole of A -pregnadiene-l7 x,21-diol-3,20-dione Zlacetate in an inert solvent comprising dioxane, and maintaining the reaction mixture at a temperature within the range of about 25 to 45 C. for a period of approximately one to four hours, thereby forming 9-chloro-17a-hydroxycorticosterone acetate.

* 7 References Cited in the file of this patent UNITED STATES PATENTS 2,634,277 1 Minlon Apr. 7, 1953 2,707,190 Farrar Apr. 26, 1955 2,763,671 Fried et al. Sept. 18, 1956 OTHER REFERENCES Fried, Jour. Am. Chem. Soc., 75, 227374 (1953). 

